Abstract
Autologous fat grafting is an effective reconstructive surgery technique; however, its success is limited by inconsistent graft retention and an environment characterized by high oxidative stress and inflammation. Adipose-derived stem cells (ADSCs) increase the survival of fat grafts, although the underlying mechanisms remain unclear. Here, TLR4−/− and Nrf2−/− mice were used to explore the effects of oxidative stress and inflammation on the viability and function of ADSCs in vitro and in vivo. Enrichment of fat grafts with ADSCs inhibited inflammatory cytokine production, enhanced growth factor levels, increased fat graft survival, downregulated NADPH oxidase (NOX)1 and 4 expression, increased vascularization and reduced ROS production in a manner dependent on toll-like receptor (TLR)-4 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Immunohistochemical analysis showed that exposure to hypoxia enhanced ADSC growth and promoted the differentiation of ADSCs into vascular endothelial cells. Hypoxia-induced inflammatory cytokine, growth factor and NOX1/4 upregulation, as well as increased ROS production and apoptosis in ADSCs were dependent on TLR4 and Nrf2, which also modulated the effect of ADSCs on promoting endothelial progenitor cell migration and angiogenesis. Western blot analyses showed that the effects of hypoxia on ADSCs were regulated by crosstalk between Nrf2 antioxidant responses and NF-κB- and TLR4-mediated inflammatory responses. Taken together, our results indicate that ADSCs can increase the survival of fat transplants through the modulation of inflammatory and oxidative responses via Nrf2 and TLR4, suggesting potential strategies to improve the use of ADSCs for cell therapy.
Highlights
Autologous fat grafting, which is the transfer of subcutaneous fat from a donor site to a recipient site, is a commonly used procedure in both cosmetic and reconstructive surgery
The results showed that adipose-derived stem cells (ADSCs) promoted the survival of fat grafts, whereas this effect was significantly decreased in Nrf[2] and TLR4 knockout mice, in which grafts did not survive after 2 months in the absence of ADSCs (Figures 2a and b)
Analysis of NOX1, NOX4 and heme oxygenase-1 (HO-1) expression in transplanted adipose tissues by real-time PCR 2 weeks after transplantation showed that ADSCs downregulated NOX1 and NOX4 in mice receiving fat grafts, and this effect was enhanced by TLR4 knockout, whereas it was suppressed by Nrf[2] knockout, which restored NOX1/4 levels to those observed in mice receiving untreated fat grafts (Figures 2c and d)
Summary
Autologous fat grafting, which is the transfer of subcutaneous fat from a donor site to a recipient site, is a commonly used procedure in both cosmetic and reconstructive surgery. Oxidative stress affects ADSCs and their regenerative capacity, and dysregulation of reactive oxygen species (ROS) production impairs ADSC expansion in vitro and the viability of engrafted ADSCs.[7] low levels of ROS were shown to activate cellular processes involved in the normal physiological function of stem cells.[8] Intracellular ROS are generated by the action of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymes (NOX) and passively by mitochondria.[9,10] Culture of ADSCs under hypoxic conditions increases their proliferative and migratory capacities and enhances the secretion of growth factors.[11,12] There are four NOX enzymes, of which NOX4 is predominantly expressed in ADSCs and modulates ROS signaling as well as the proliferation and differentiation of ADSCs.[13]. TLR4− / − and Nrf2− / − mice were used to explore the effects of oxidative stress and inflammation on the viability and function of ADSCs and their role in improving the survival of fat grafts in vitro and in vivo
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